Patients with various bladder disorders including hyperreflexic voiding dysfunction and secondary urge incontinence are typically treated with anticholinergic and antispasmodic agents, such as oxybutynin chloride (benzeneacetic acid, .alpha.-cyclohexyl-.alpha.-hydroxy-, 4-(diethylamino)-2-butynyl ester hydrochoride, (.+-.)). Oxybutynin chloride (OC) is available in syrup and table form (United States Pharmacopoeia Official Monographs 23:1127-1129). However, many patients do not respond to these medications when taken orally or have unacceptable side effects that limit their use. Such side effects include dryness of the mouth, disturbance of accommodation and increased constipation.
OC has been administered directly to the bladder via a catheter (intravesical administration). Brendler et al. (J. Urology 141:1350-1352, 1989) dissolved 5 mg. tablets of OC in water and instilled the resulting solution via a catheter into the bladder of patients with persistent urge incontinence twice daily. The solution was retained for 30 minutes. Madersbacher et al. (Paraplegia 29:84-90, 1991) instilled the same OC solution via catheter into the bladder to treat detrusor hyperreflexia in patients with spinal cord lesions. Greenfield et al. (J. Urology 146:532-534, 1991) dissolved 5 mg. tablets of OC in 10 ml of saline and administered the resulting solution via catheter to the bladder of patients with hypertonic, hyperreflexive bladders. Massad et al. (J. Urology 143:595-597, 1992) examined the pharmacokinetics of intravesical and oral OC. Oxybutinin chloride tablets were crushed and dissolved in sterile water (7.5 mg/30 ml). The resulting solution was administered orally or intravesically to patients with uninhibited detrusor activity and/or poor bladder compliance. The authors concluded that intravesical OC was well tolerated, efficacious and rapidly absorbed, resulting in plasma concentrations markedly higher than after oral administration. Weese et al. (Urology 41:527-530, 1993) dissolved 5 mg OC tablets in 30 cc sterile water and instilled the resulting solution into the bladders of patients who were incontinent secondary to uninhibited detrusor contractions and had failed oral anticholinergic therapy. Other studies have also been described using OC tablets dissolved in water or saline for installation into the bladder of patients with bladder dysfunction (Prasad et al., British J Urology 72:719-722, 1993; Connor et al., J. Urology 151:1045-1047, 1994; Kaplinsky et al., J. Urology 156:753-756, 1996; Painter et al., J Urology 156:1459-1462, 1996; Palmer et al., J Urology 157:638-640, 1997). In all of these studies, OC tablets are dissolved in saline or water at a near neutral pH, delivered to the bladder via a catheter, and allowed to remain in the bladder for several hours prior to removal. In these studies, the concentration range of OC used was between 0.17 and 0.5 mg/ml. Bonney et al., J. Urology 150:1522-1525, 1993, intravesically administered OC dissolved in sterile saline to rats at three doses: 0.25 mg/ml, 2.5 mg/ml and 25 mg/ml, to determine the effects of drug concentration on mucosal or bladder wall change, and on urinary infection. The authors concluded that in the highest dose group (25 mg/ml), systemic absorption from the bladder caused weight loss and cachexia.
Although the OC solutions described above are suitable for temporary installation into the bladder, they are not sufficiently stable for extended delivery into the bladder over several weeks or months. The present invention provides stable OC compositions for use in intravesical infuser devices for extended diffusion into the bladder.